CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma
CREBBP cooperates with the cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory diffuse large B-cell lymphoma
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CREBBP 与细胞周期机制合作，减弱复发/难治性弥漫性大 B 细胞淋巴瘤对西达酰胺的敏感性
DOI：
10.1016/j.canlet.2021.09.002
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发表时间：
2021-09-13
期刊：
影响因子：
9.7
通讯作者：
Tan, Jing
中科院分区：
文献类型：
--
作者：
Sun, Yichen;Gao, Yan;Tan, Jing
弥漫性大B细胞淋巴瘤(DLBCL)经常表现出组蛋白乙酰转移酶CREBBP的失活突变，这突显了将CREBBP缺陷作为一种治疗策略的吸引力。在这项研究中，我们证明了一种新型的组蛋白脱乙酰酶(HDAC)抑制剂Chidamide对部分复发/难治性DLBCL患者是有效的，总有效率(ORR)为25.0%，完全有效率(CR)为15.0%。然而，由于大多数患者表现出耐药性，对氯硝胺的临床反应仍然很差，这阻碍了该药物的临床应用。体外和体内的功能研究表明，CREBBP功能的丧失与Chidamide敏感性有关，这与细胞周期机制的调节有关。一项针对细胞周期调节因子的130种激酶抑制剂的联合药物筛选确定了AURKA抑制剂，它在细胞周期中抑制G2/M转换，是协同增强CHIDAME在CREBBP熟练的DLBCL细胞中的抗肿瘤作用的首选药物。我们的研究表明，CREBBP失活可以作为一个潜在的生物标记物来预测胆碱胺的敏感性，而AURKA抑制剂和胆碱胺的联合治疗是治疗复发/难治性DLBCL的一种新的治疗策略。
Diffuse large B-cell lymphoma (DLBCL) exhibits frequent inactivating mutations of the histone acetyltransferase CREBBP, highlighting the attractiveness of targeting CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor, as most patients exhibit resistance, hampering the clinical utility of the drug. Functional in vitro and in vivo studies have shown that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulation of the cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibit the G2/M transition during the cell cycle, as top candidates that synergistically enhanced the antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrates that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while combination of an AURKA inhibitor and chidamide is a novel therapeutic strategy for the treatment of relapsed/ refractory DLBCL.